Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers

Abstract

Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers. We identified a previously unreported trisulfated sterol, i.e., topsentinol L trisulfate (TLT), which exhibited increased efficacy against BL-CL breast cancers relative to luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL cell lines revealed its ability to inhibit activation of AMP-activated protein kinase (AMPK) and checkpoint kinase 1 (CHK1) and to promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive.

High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

“…Within the CCLE drug screen, CHK1 inhibitors presented promising effects against basal cell lines. This result is supported by a recent study that showed CHK1 inhibitors being effective against basal-like breast cancer [43]. Interestingly, HDAC1/2 are known to sustain the phosphorylation and thus the activity of the checkpoint kinases CHK1/2, providing a link between these targets in BLCA [44].…”

Breast cancer heterogeneity and its implication in personalized precision therapy

“…Topsentinol L trisulfate can inhibit the activation of AMP-activated protein kinase and checkpoint kinase 1 and promote activation of p38 in claudin-low breast cancer. Topsentinol L trisulfate has higher efficacy against claudin-low breast cancer than other types [ 281 ]. Most claudin-low breast tumors are reported to be ER – , PR – , and HER2 – ; therefore, the treatment of TNBC can play a guiding role in the treatment of claudin-low breast cancer to a certain extent [ 30 , 282 ].…”